Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is however still known concerning epigenetic changes occurring in thymomas from MG individuals. The study aims: to shed light on the contribution of DNA methylation to the development of thymoma associated MG (TAMG) by the detection of gene-specific methylation levels in promoters of MTHFR, DNMT1, DNMT3A, DNMT3B, AIRE, MGMT, hMLH1, RASSF1A, CDKN2A genes and detection of global methylation by means of LINE1 methylation analysis in blood, tumor tissue, and adjacent thymus tissue; to understand if DNA promoter methylation influences gene expression and if it correlates with clinicopathological features of patients; to understand if some of polymorphisms in genes of folate metabolism, a key pathway involved in providing methyl groups necessary for DNA methylation, correlate with thymoma risk and if these polymorphisms influence the methylation levels of chosen genes. Both MTHFR and DNMT3A promoters showed significant higher methylation levels in tumor tissue respect to blood, while AIRE showed an opposite trend. MTHFR showed also significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells, while AIRE showed lower methylation levels in healthy tissue respect to blood. Moreover a negative correlation between MTHFR promoter methylation and gene expression in a small subgroup was found. All the other studied genes were largely hypomethylated both in blood and in tumor tissue, and the mean methylation levels were no higher than 2%. TAMG showed global DNA hypomethylation, in fact LINE1 resulted hypomethylated in tumor tissue respect to blood. Correlating clinicopathological features of patients with methylation levels, correlations between LINE1 and thymoma histology, Masaoka classification and MG Osserman one in tumor tissue were found. hMLH1 methylation levels increased with age. Comparing genotype and allele frequencies between normal thymus patients and TAMG patients, significant decrease of TYMS 28bp 2R allele frequency in patients with thymoma with respect to normal thymus was observed. The TYMS 28bp 2R2R genotype was associated with decreased risk to develop a thymoma among MG patients. Moreover, it was noticed that polymorphisms of gene involved in one-carbon metabolism could affect DNA methylation, in fact statistically significant correlations between the MTRR 66A>G polymorphism and MTHFR and hMLH1 promoter methylation in tumor tissue and DNMT1 in blood, between the DNMT3B -579TT genotype and higher promoter methylation levels of DNMT3B and hMLH1 in tumor tissue and blood were found; the same happens for DNMT3B -149TT genotype related to DNMT3B methylation in thymoma tissue and blood. The present study suggests that epigenetic changes, in term of gene specific methylation and global hypomethylation, could be involved in TAMG and that DNA methylation could influence gene expression and could be partially influenced by polymorphisms in folate metabolism genes.

Lopomo, A. (2017). Genetic and epigenetic analyses in thymomas of patients with Myasthenia Gravis.

Genetic and epigenetic analyses in thymomas of patients with Myasthenia Gravis

LOPOMO, ANGELA
2017-01-01

Abstract

Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is however still known concerning epigenetic changes occurring in thymomas from MG individuals. The study aims: to shed light on the contribution of DNA methylation to the development of thymoma associated MG (TAMG) by the detection of gene-specific methylation levels in promoters of MTHFR, DNMT1, DNMT3A, DNMT3B, AIRE, MGMT, hMLH1, RASSF1A, CDKN2A genes and detection of global methylation by means of LINE1 methylation analysis in blood, tumor tissue, and adjacent thymus tissue; to understand if DNA promoter methylation influences gene expression and if it correlates with clinicopathological features of patients; to understand if some of polymorphisms in genes of folate metabolism, a key pathway involved in providing methyl groups necessary for DNA methylation, correlate with thymoma risk and if these polymorphisms influence the methylation levels of chosen genes. Both MTHFR and DNMT3A promoters showed significant higher methylation levels in tumor tissue respect to blood, while AIRE showed an opposite trend. MTHFR showed also significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells, while AIRE showed lower methylation levels in healthy tissue respect to blood. Moreover a negative correlation between MTHFR promoter methylation and gene expression in a small subgroup was found. All the other studied genes were largely hypomethylated both in blood and in tumor tissue, and the mean methylation levels were no higher than 2%. TAMG showed global DNA hypomethylation, in fact LINE1 resulted hypomethylated in tumor tissue respect to blood. Correlating clinicopathological features of patients with methylation levels, correlations between LINE1 and thymoma histology, Masaoka classification and MG Osserman one in tumor tissue were found. hMLH1 methylation levels increased with age. Comparing genotype and allele frequencies between normal thymus patients and TAMG patients, significant decrease of TYMS 28bp 2R allele frequency in patients with thymoma with respect to normal thymus was observed. The TYMS 28bp 2R2R genotype was associated with decreased risk to develop a thymoma among MG patients. Moreover, it was noticed that polymorphisms of gene involved in one-carbon metabolism could affect DNA methylation, in fact statistically significant correlations between the MTRR 66A>G polymorphism and MTHFR and hMLH1 promoter methylation in tumor tissue and DNMT1 in blood, between the DNMT3B -579TT genotype and higher promoter methylation levels of DNMT3B and hMLH1 in tumor tissue and blood were found; the same happens for DNMT3B -149TT genotype related to DNMT3B methylation in thymoma tissue and blood. The present study suggests that epigenetic changes, in term of gene specific methylation and global hypomethylation, could be involved in TAMG and that DNA methylation could influence gene expression and could be partially influenced by polymorphisms in folate metabolism genes.
2017
Lopomo, A. (2017). Genetic and epigenetic analyses in thymomas of patients with Myasthenia Gravis.
Lopomo, Angela
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1005995
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